Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke
Year: 2015
Type: article
Study design: Observational Study
Abstract: IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk. OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis). RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.
Source: JAMA Neurology
Authors: Paul L. Auer, Mike Nalls, James F. Meschia, Bradford B. Worrall, W. T. Longstreth, Sudha Seshadri, Charles Kooperberg, Kathleen M. Burger, Christopher S. Carlson, Cara L. Carty, Wei-Min Chen, L. Adrienne Cupples, Anita L. DeStefano, Myriam Fornage, John Hardy, Li Hsu, Rebecca D. Jackson, Gail P. Jarvik, Daniel S. Kim, Kamakshi Lakshminarayan, Leslie A. Lange, Ani Manichaikul, Aaron R. Quinlan, Andrew B. Singleton, Timothy A. Thornton, Deborah A. Nickerson, Ulrike Peters, Stephen S. Rich
Institutions: Fred Hutch Cancer Center, University of Wisconsin–Milwaukee, National Institutes of Health, National Institute on Aging, Mayo Clinic, Mayo Clinic in Florida, University of Virginia, University of Washington, Boston University, George Washington University Hospital, The University of Texas Health Science Center at Houston, University College London, The Ohio State University, University of Minnesota, University of North Carolina at Chapel Hill
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, U.S. Public Health Service, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: CARDIA, FHCRC High-Performance Computing Cluster, G1170157101, G1186681542, G1194337659, G1220223050, G1241292848, Comprehensive Sequencing and Analysis of Variation in NHLBI Cohorts, G1261793039, MESA, CORONARY HEART DISEASE AND STROKE, G1276754516, G128083951, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, JACKSON HEART STUDY, G1324971107, G1325221871, G1332411685, UC Davis Alzheimer's Disease Core Center, G1379949353, G1409423729, CARDIA, G1609126075, CORONARY HEART DISEASE AND STROKE, G1640378483, CARDIA, Severe Asthma and the Glucocorticoid Receptor Complex, G191650467, G1947136479, G1955273565, G1979271746, G1992403660, G2094546735, Atherosclerosis Risk in Communities Study (ARIC), G2125475513, G2144938473, G215333750, The EVE Asthma Genetics Consortium: Building Upon GWAS, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2194386449, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G22458031, G2273349799, Northwest Genomics Center, G232264632, G232440474, G2391884931, G2412562481, MESA, G247538147, CARDIA, G250409792, G250621538, CCSP FIELD CENTER, G25881238, G2600151244, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G2644038179, G265355594, COMMUNITY AND COHORT SURVEILLANCE PROGRAM, ARRA - NHLBI Lung Cohorts Sequencing Project, RECRUITMENT EXPERIENCE IN NHLBI CLINICAL TRIALS, MESA, G2837638605, G290884426, G291913881, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, JACKSON HEART STUDY, G3045517347, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, Siblings With Ischemic Stroke Study (SWISS), G3107571658, Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortium, G3186385431, G3220743633, G3236609591, G3396487927, G3497998071, G3545534745, G3550174423, G36433118, G3647016462, Institute of Translational Health Sciences, G3787787485, MESA, G390162502, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, G411804357, G412187901, G412671775, G4165892905, Coronary Artery Risk Development in Young Adults (CARDIA) Study - Field Center, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), Atherosclerosis Risk in Communities Study (ARIC), OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, G49077879, MESA, G500195777, G50822097, G510023084, G5164707915, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, G528395701, G5302475043, G538503247, Biomarkers of Vascular Disease in Scleroderma, G5479317095, G5547620395, G5558075022, G5602787650, G5624510383, (2 of 2) Genetic Epidemiology of COPD, Atherosclerosis Risk in Communities Study (ARIC), G581887176, G582705428, CHARGE consortium: omics discovery for CVD and aging phenotypes, CHS Events Follow-up Study, G619791618, G6203107232, G6226795708, The Framingham Heart Study, MESA, G6520056932, Human Exome Sequencing in Six Well-Phenotyped NHLBI Cohorts, G66341962, CHS-Transition Phase, G673128162, WHI Sequencing Project (WHISP), G6889087017, Ethical and Social Issues in the Study of Genetics of Complex Traits, G691201058, G7008601573, G700897395, G715477388, Genetic risks for ALI in ARDSnet and the iSPAAR Consortium, G7176672723, General Clinical Research Center, MESA, ISGS: The Ischemic Stroke Genetics Study, G786153652, G78770644, G793702358, Molecular Phenotypes for Cystic Fibrosis Lung Disease, G812579647, G831158291, G8486527673, G8536616440, G8575659492, Prognostic Factors, Genetics, and Therapy in PAH-SSD, G882825004, Molecular Determinants of Pulmonary Arterial Hypertension, G9000015445, Cancer Center Support Grant, G91218548, EARLY INTERVENTION/CHRONIC OBSTRUCTIVE PULMONARY DISEASE, JACKSON HEART STUDY, Atherosclerosis Risk in Communities Study (ARIC), G991334795
OpenAlex ID: W2139892622